chr2-118974364-G-A

Position:

• chr2-118974364-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006770.4(MARCO):​c.492G>A​(p.Met164Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,454,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MARCO NM_006770.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.22

Genes affected

MARCO (HGNC:6895): (macrophage receptor with collagenous structure) The protein encoded by this gene is a member of the class A scavenger receptor family and is part of the innate antimicrobial immune system. The protein may bind both Gram-negative and Gram-positive bacteria via an extracellular, C-terminal, scavenger receptor cysteine-rich (SRCR) domain. In addition to short cytoplasmic and transmembrane domains, there is an extracellular spacer domain and a long, extracellular collagenous domain. The protein may form a trimeric molecule by the association of the collagenous domains of three identical polypeptide chains. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049111307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARCO	NM_006770.4	c.492G>A	p.Met164Ile	missense_variant	5/17	ENST00000327097.5
MARCO	XM_011512082.3	c.492G>A	p.Met164Ile	missense_variant	5/17
MARCO	XM_011512083.4	c.129G>A	p.Met43Ile	missense_variant	2/14
MARCO	XM_017005171.3	c.492G>A	p.Met164Ile	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARCO	ENST00000327097.5	c.492G>A	p.Met164Ile	missense_variant	5/17	1	NM_006770.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454648 Hom.: 0 Cov.: 32 AF XY: 0.00000692 AC XY: 5 AN XY: 722828

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

The c.492G>A (p.M164I) alteration is located in exon 5 (coding exon 5) of the MARCO gene. This alteration results from a G to A substitution at nucleotide position 492, causing the methionine (M) at amino acid position 164 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.068
DANN	Benign	0.45
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.27	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.13
Sift	Benign	0.28	T
Sift4G	Benign	0.20	T
Polyphen		0.036	B
Vest4		0.16
MutPred		0.35		Gain of ubiquitination at K159 (P = 0.1051);
MVP		0.24
MPC		0.063
ClinPred		0.71	D
GERP RS		-7.9
Varity_R		0.085
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1185170201; hg19: chr2-119731940;